@article {1825, title = {HIV-1 induces NALP3-inflammasome expression and interleukin-1β secretion in dendritic cells from healthy individuals but not from HIV-positive patients.}, journal = {AIDS}, volume = {26}, year = {2012}, month = {2012 Jan 2}, pages = {11-8}, abstract = {

OBJECTIVE: NALP3-inflammasome is an innate mechanism, alternative to type-1 interferon, which is able to recognize nucleic acids and viruses in the cytoplasm and to induce pro-inflammatory response. Here, we hypothesized the involvement of inflammasome in the early defense against HIV-1 and in the full maturation of dendritic cells: for this, we evaluated the response of dendritic cells pulsed with HIV-1 in terms of inflammasome activation in healthy donors. Moreover, inflammasome response to HIV was evaluated in HIV-infected individuals.

DESIGN AND METHODS: Monocyte-derived dendritic cells isolated from 20 healthy individuals (HC-DC) and 20 HIV-1-infected patients (HIV-DC) were pulsed with alditrithiol-2-inactivated HIV-1. We then analyzed inflammasome genes expression and interleukin-1β (IL-1β) secretion.

RESULTS: In HC-DC, HIV-1 induced higher NLRP3/NALP3 mRNA expression compared with other inflammasome genes such as NALP1/NLRP1 or IPAF/NLRC4 (P < 0.001). This augmented expression was accompanied by CASP1-increased and IL1B-increased mRNA levels and by a significant increment of IL-1β secretion (P < 0.05). Otherwise, HIV-1 failed to activate inflammasome and cytokine production in HIV-DC. HIV-DC showed an increased NLRP3/NALP3 basal expression, suggesting a chronic inflammatory profile of patients{\textquoteright} immune cells.

CONCLUSION: HIV-1 was able to induce a NALP3-inflammasome response in healthy individuals, indicating that this inflammasome could play a role in the first steps of HIV-1 infection; the consequent inflammatory process may be important for directing host immune response against the virus and/or disease progression. HIV-DC seemed to be chronically activated, but unresponsive against pathogens. Our findings could be of interest considering the ongoing research about dendritic cell manipulation and therapeutic strategies for AIDS involving dendritic cell-based immune-vaccines.

}, keywords = {Acquired Immunodeficiency Syndrome, Adult, Brazil, Carrier Proteins, Caspase 1, Cells, Cultured, Dendritic Cells, DNA, Viral, Female, HIV-1, Humans, Immunity, Innate, Inflammasomes, Interleukin-1beta, Male, Tumor Necrosis Factor-alpha}, issn = {1473-5571}, doi = {10.1097/QAD.0b013e32834d697f}, author = {Pontillo, Alessandra and Silva, Lais T and Oshiro, Telma M and Finazzo, Claudia and Crovella, Sergio and Duarte, Alberto J S} } @article {1824, title = {High incidence of NLRP3 somatic mosaicism in patients with chronic infantile neurologic, cutaneous, articular syndrome: results of an International Multicenter Collaborative Study.}, journal = {Arthritis Rheum}, volume = {63}, year = {2011}, month = {2011 Nov}, pages = {3625-32}, abstract = {

OBJECTIVE: Chronic infantile neurologic, cutaneous, articular (CINCA) syndrome, also known as neonatal-onset multisystem inflammatory disease (NOMID), is a dominantly inherited systemic autoinflammatory disease. Although heterozygous germline gain-of-function NLRP3 mutations are a known cause of this disease, conventional genetic analyses fail to detect disease-causing mutations in \~{}40\% of patients. Since somatic NLRP3 mosaicism has been detected in several mutation-negative NOMID/CINCA syndrome patients, we undertook this study to determine the precise contribution of somatic NLRP3 mosaicism to the etiology of NOMID/CINCA syndrome.

METHODS: An international case-control study was performed to detect somatic NLRP3 mosaicism in NOMID/CINCA syndrome patients who had shown no mutation during conventional sequencing. Subcloning and sequencing of NLRP3 was performed in these mutation-negative NOMID/CINCA syndrome patients and their healthy relatives. Clinical features were analyzed to identify potential genotype-phenotype associations.

RESULTS: Somatic NLRP3 mosaicism was identified in 18 of the 26 patients (69.2\%). Estimates of the level of mosaicism ranged from 4.2\% to 35.8\% (mean {\textpm} SD 12.1 {\textpm} 7.9\%). Mosaicism was not detected in any of the 19 healthy relatives (18 of 26 patients versus 0 of 19 relatives; P < 0.0001). In vitro functional assays indicated that the detected somatic NLRP3 mutations had disease-causing functional effects. No differences in NLRP3 mosaicism were detected between different cell lineages. Among nondescript clinical features, a lower incidence of mental retardation was noted in patients with somatic mosaicism. Genotype-matched comparison confirmed that patients with somatic NLRP3 mosaicism presented with milder neurologic symptoms.

CONCLUSION: Somatic NLRP3 mutations were identified in 69.2\% of patients with mutation-negative NOMID/CINCA syndrome. This indicates that somatic NLRP3 mosaicism is a major cause of NOMID/CINCA syndrome.

}, keywords = {Adolescent, Adult, Carrier Proteins, Case-Control Studies, Child, Child, Preschool, Cryopyrin-Associated Periodic Syndromes, Female, Genetic Association Studies, Humans, Infant, Male, Mosaicism}, issn = {1529-0131}, doi = {10.1002/art.30512}, author = {Tanaka, Naoko and Izawa, Kazushi and Saito, Megumu K and Sakuma, Mio and Oshima, Koichi and Ohara, Osamu and Nishikomori, Ryuta and Morimoto, Takeshi and Kambe, Naotomo and Goldbach-Mansky, Raphaela and Aksentijevich, Ivona and de Saint Basile, Genevi{\`e}ve and Neven, B{\'e}n{\'e}dicte and van Gijn, Mari{\"e}lle and Frenkel, Joost and Ar{\'o}stegui, Juan I and Yag{\"u}e, Jordi and Merino, Rosa and Iba{\~n}ez, Mercedes and Pontillo, Alessandra and Takada, Hidetoshi and Imagawa, Tomoyuki and Kawai, Tomoki and Yasumi, Takahiro and Nakahata, Tatsutoshi and Heike, Toshio} } @article {1683, title = {Histatins in non-human primates: gene variations and functional effects.}, journal = {Protein Pept Lett}, volume = {17}, year = {2010}, month = {2010 Jul}, pages = {909-18}, abstract = {

Human histatins are histidine-rich, low molecular weight salivary proteins that contribute to the immune system of the oral cavity. In this work, nucleotide sequences of the HIS1 (coding for histatin 1) and HIS2 (coding for histatin 3) genes, homologous to the human ones, have been sequenced and analysed in five primates species including Great Ape, Hylobatidae and Cercopithecidae. In HIS1, the region corresponding to the putative mature peptide shows a premature stop codon in Macaca and Cercopithecus, while HIS2 a six codon insertion in the Cercopithecidae. Histatin 5, a 24-residue peptide derived from histatin 3, is the most antimicrobially active among human histatins, thus macaque and nomascus orthologues of histatin 5 were selected for chemical synthesis and functional characterization, in comparison to the human peptide. All synthesized histatins are predicted to be poorly amphipathic, depending on the charged state of His residues and assume partially a-helical conformations only in lipophilic conditions. Antimicrobial assays against Candida and Criptococcus spp. indicate somewhat different spectra of in vitro activity against the tested fungi. We have described HIS1 and HIS2 gene variations in primates and have analysed their functional effects on selected Hst5 orthologues. The human antimicrobial peptide has been proposed to represent an important lead for new generation of antimicrobial compounds for the treatment of oral mycoses, thus the information from the non-human primates histatins studied may aid strategies for drugs design.

}, keywords = {Amino Acid Sequence, Animals, Anti-Infective Agents, Base Sequence, Candida, Catarrhini, Cell Proliferation, Computational Biology, Cryptococcus, Genetic Variation, Histatins, Humans, Molecular Sequence Data, Phylogeny, Sequence Alignment, Sequence Analysis, DNA}, issn = {1875-5305}, author = {Padovan, Lara and Segat, Ludovica and Pontillo, Alessandra and Antcheva, Nikolinka and Tossi, Alessandro and Crovella, Sergio} }